There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin, and is usuall closely associated with obesity. Recent data suggest an inflammatory link between obesity and insulin resistance. We hypothesize that the induction of a counter-inflammatory program downstream of NF?B plays a key role in preserving energy storage, reducing energy expenditure and ensuring that insulin resistance is maintained during obesity. To this end, we have searched for inhibitors of the noncanonical IKK's TBK1 and IKK?, and plan to develop these as new therapeutic modalities. We will pursue this plan with three aims: 1) We will development analogs of the newly discovered inhibitor amlexanox with increased potency and metabolic stability, using both medicinal chemistry and structure- based design approaches; 2) We will develop novel inhibitors of IKK? and TBK1 that represent new chemical entities, driven by increased potency, improved pharmaceutical properties and in vivo activity in mouse models of obese type 2 diabetes; and 3) In order to support the clinical development of these new compounds, we will develop in vivo biomarkers for IKK?/TBK1 inhibition.